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Drug Quality &Resistance Bill Brieger | 14 Feb 2009 08:41 am

ACT Treatment Failure – reality today … or tomorrow

The ‘F’ word has appeared in peer reviewed malaria literature. “Failure of artesunate-mefloquine combination therapy for uncomplicated Plasmodium falciparum malaria in southern Cambodia,” reads the title of a new article in Malaria Journal. The authors concluded that, “It is unclear whether the treatment failures are due solely to mefloquine resistance or to artesunate resistance as well. The findings of delayed clearance times and elevated artesunate IC50 suggest that artesunate resistance may be emerging on a background of mefloquine resistance.”

In narrowing down an explanation for treatment failure, the authors considered the following:

  • Adulterated and counterfeit drugs are on the market, but it was unlikely that these entered into their study
  • Mefloquine dosage ideally varies by weight, and some could have been underdosed, but again analysis shows this was not a factor

The authors also surmised that if resistance to mefloquine is at play, this may expose the patient to only a three-day dose of the artesunate, which then would effectively make artesunate a monotherapy and open to provoking resistance at that dose.

Lim and colleagues consider how resistance to artemisinin drugs could develop in artemether-lumefantrine (AL). coartem-sm.JPG Challenges to absorption of lumefantrine exist and may be related to diet. Here again, the artemisin drug would effectively become 3-day dose of monotherapy, if the partner in the combination was compromised.

Fortunately Premji et al. reported in Africa that “food consumption is adequate post-weaning (and) it appears that only a very small amount of dietary fat is necessary to ensure optimal efficacy with AL and that the fat content of standard meals or breast milk in sub-Saharan Africa is adequate.”

Could home management be a tipping point for ACT resistance.  Data from Ajayi et al. “provides encouraging data on parasitological outcomes of children treated with ACT in the context of HMM and adds to the evidence base for HMM as a public health strategy as well as for scaling-up implementation of HMM with ACTs.” A strong health education component to home management is still necessary.

After modeling the scenarios for ACT resistance, Pongtavornpinyo and co-researchers offer a prescription for action.  They conclude that, “The spread of drug resistance could be slowed down by controlling presumptive drug use and avoiding the use of combination therapies containing drugs with mismatched half-lives, together with reducing malaria transmission through vector control measures.”

Pongtavornpinyo also noted that resistance is more likely to develop in low transmission areas such as found in studies from Southeast Asia mentioned above. Even in high transmission areas, “high ACT coverage alone cannot reduce malaria transmission unless it is used together with vector-control measures.”

Unfortunately at present unavailability of ACTs may be a bigger problem in these high transmission areas, such as the frequent stock-outs in Uganda reported by Start News. This is despite several years of Global Fund support for malaria control in Uganda. Purchasing the new ACTs in commercial pharmacies is too expensive for most, and so people resort to buying the older and cheaper drugs for which there is resistance.

Either way – whether resistance to artemisinin develops tomorrow or people are forced to take cheaper but less effective drugs today – the patient suffers.

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